The objective of this study is to examine how the transcription factor CREB modulates hepatic insulin sensitivity. During fasting, CREB induces gluconeogenic genes in liver, which are repressed in response to insulin after a meal. The proposed studies will test the hypothesis that during fasting CREB primes the liver for efficient cessation of gluconeogenesis by activating expression of genes in the insulin signaling pathway, including the insulin receptor IRS-2. Specifically, I will investigate the molecular mechanisms of CREB- dependent transcription of insulin pathway genes and how this regulatory loop modulates glucose homeostasis. I will assess the requirements of CREB, its co-activator TORC2, and Foxo transcription factors for transcription of these genes by RNAi-mediated knockdown in primary hepatocytes. I will also examine the effects of this pathway on fasting hepatic insulin sensitivity by acute knockdown of CREB, TORC2 and Foxo by adenovirus infection in vivo followed by measurements of fasting blood glucose levels, insulin tolerance, and hepatic glucose output. This study will contribute to an understanding of the mechanisms regulating the balance between glucose output and storage in fasted versus fed states. [unreadable] [unreadable] [unreadable]